Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[NH2:31])[N:23]=2)=[CH:15][CH:14]=1)(=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8].N1C=CC=CC=1>ClCCl>[C:6]([O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[NH:31][S:2]([CH3:1])(=[O:4])=[O:3])[N:23]=2)=[CH:17][CH:18]=1)(=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)C(=O)Oc1ccc(-c2nnn(Cc3ccccc3N)n2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1ccc(-c2nnn(Cc3ccccc3NS(C)(=O)=O)n2)cc1
Reaction time: 15 h
Yield: 69.9 %

Procedure:
Methanesulfonyl chloride (114.5 mg) was added to a solution of 4-[2-(2-aminobenzyl)tetrazol-5-yl]phenyl pivalate (0.351 g), obtained in example 78, and pyridine (79 mg) in dichloromethane (2 ml) under ice cooling, and stirring was continued for 15 h. The mixture was washed with water, dried and evaporated to dryness. The residue was purified by column chromatography on silica gel with ethyl acetate-hexane (1/2) as an eluate. Recrystallization from ethyl acetate-hexane gave 300 mg (70%) of the title compound.
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].[NH2:8][C@@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@H:10]1[NH:18][C:19]([C:21]1[NH:25][C:24]2[C:26]([Cl:30])=[C:27]([Cl:29])[S:28][C:23]=2[CH:22]=1)=[O:20].C(O)=O.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:29][C:27]1[S:28][C:23]2[CH:22]=[C:21]([C:19]([NH:18][C@@H:10]3[CH2:11][C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C@H:9]3[NH:8][CH:3]=[O:4])=[O:20])[NH:25][C:24]=2[C:26]=1[Cl:30]
Reactant: O=C(O)C(F)(F)F
Reactant: N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O=CO
Solvent: CCN(C(C)C)C(C)C
Product: O=CN[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Reaction time: 0.08 h
Yield: 88.8 %

Procedure:
N-[(1R,2R)-1-Amino-2,3-dihydro-1H-inden-2-yl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide trifluoroacetic acid salt (Method 8, 240 mg, 0.5 mmol), formic acid (50 μL, 1.4 mmol), DIPEA (174 μL, 1.0 mmol) and HOBT (67 mg, 0.5 mmol) were dissolved in DCM (5 ml), stirred for 5 mins, EDCI (120 mg, 0.625 mmol) added and the reaction stirred for 1 hr. Formic acid (50 μL, 1.4 mmol) and EDCI (240 mg, 1.25 mmol) were added, the reaction stirred for 2 hours and the volatiles removed by evaporation under reduced pressure. The residue was dissolved in EtOAc (20 mL), washed with water (2×10 mL), brine (10 mL), dried (MgSO4) and the volatiles removed by evaporation under reduced pressure. The residue was purified by column chromatography (2:1 EtOAc:Hexane) to afford the title compound (175 mg, 89%) as a white foam.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1.[H-].[Na+].O>C1COCC1>[N:23]1[CH:24]=[CH:25][C:20]([C:16]2[CH:15]=[C:14]([NH:13][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=3[N+:10]([O-:12])=[O:11])[CH:19]=[CH:18][CH:17]=2)=[N:21][CH:22]=1
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1cccc(-c2ccncn2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(Nc2cccc(-c3ccncn3)c2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.6 %

Procedure:
To a mixture of 4-chloro-3-nitrobenzonitril (5.5 g, 30 mmol) and (58) (5.1 g, 30 mmol) in THF (120 ml) was added sodium hydride (2.3 g, 50% suspension in mineral oil). After stirring at room temperature for 2 days, the mixture was poured into water and extracted with CH2Cl2. The extract was concentrated under reduced pressure and the residue was triturated with diethylether to yield crystalline (59) (9.2 g, 96%).
Reaction SMILES: [CH2:1]([P:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[Cl:14][CH2:15][C:16]1[C:17]([CH2:22][Cl:23])=[CH:18][CH:19]=[CH:20][CH:21]=1>C1(C)C=CC=CC=1>[Cl-:14].[Cl:23][CH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][P+:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: ClCc1ccccc1CCl
Reactant: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCCC[P+](CCCC)(CCCC)Cc1ccccc1CCl
Product: [Cl-]
Temperature: 25 °C

Procedure:
A mixture of tri-n-butylphosphine (18.9 g, 103.8 mmol) in toluene (50 mL) was added dropwise to a mixture of α,α'-dichloro-o-xylene (7.0 g, 34.6 mmol) in toluene (200 mL) under argon gas. The reaction mixture was allowed to stir for several days at room temperature under argon, at which time TLC examination showed completion of reaction. Toluene was removed under reduced pressure to give an oily residue. The above oily residue was washed with toluene/hexane (50/50 (v/v), 4×100 mL), and then dried to give a colorless oil. 1H NMR (CDCl3) δ0.89 (t, 9H), 1.43 (m, 12H), 2.52 (m, 6H), 4.41 (d, 2H), 4.88 (s, 2H), 7.33 (m, 2H), 7.4 5 (m, 1H), 7.52 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:21]([CH3:23])[CH3:22])[CH:13]([OH:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[CH3:32][C:33]([Si:36](OS(C(F)(F)F)(=O)=O)([CH3:38])[CH3:37])([CH3:35])[CH3:34]>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:21]([CH3:22])[CH3:23])[CH:13]([O:20][Si:36]([C:33]([CH3:35])([CH3:34])[CH3:32])([CH3:38])[CH3:37])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)CC(O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)CC(O[Si](C)(C)C(C)(C)C)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Yield: 88.7 %

Procedure:
Under an argon atmosphere, to a solution (228 mL) of ethyl (4S)-4-{[(benzyloxy)carbonyl]amino}-3-hydroxy-5-methylhexanoate (14.74 g) in dehydrated THF was added 2,6-lutidine (7.33 g) with stirring under ice-cooling, and tert-butyl dimethylsilyl trifluoromethanesulfonate (14.46 g) was added dropwise. The mixture was gradually warmed to room temperature and stirred for 1.5 hr. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=19/1→4/1) to give ethyl (4S)-4-{[(benzyloxy)carbonyl]amino}-3-{[tert-butyl(dimethyl)silyl]oxy}-5-methylhexanoate as colorless oil (yield: 17.7 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)[OH:8])([O-:3])=[O:2].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:13]([O:11][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][C:7]=1[O:8][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCBr
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Product: CCCCCCCCCCOc1ccc([N+](=O)[O-])cc1OCCCCCCCCCC

Procedure:
Using this procedure, the reaction of 4-nitrocatechol with 1-bromodecane gave 3,4-bis(decyloxy)nitrobenzene (mp 60°-61°, Anal. Calcd for C26H45NO4 : C, 71.68; H, 10.41; N, 3.22. Found: C, 71.63; H, 10.55; N, 3.21.
Reaction SMILES: [OH-:1].[K+].[CH2:3]([C:6](=[CH:9][CH2:10][CH3:11])[C:7]#N)[CH2:4][CH3:5].N.Cl.[OH2:14]>CCCCCC.OCC(CO)O>[CH2:3](/[C:6](=[CH:9]\[CH2:10][CH3:11])/[C:7]([OH:14])=[O:1])[CH2:4][CH3:5]
Reactant: [OH-]
Reactant: O
Reactant: CCC=C(C#N)CCC
Agent: Cl
Agent: N
Agent: [K+]
Solvent: OCC(O)CO
Solvent: CCCCCC
Product: CC/C=C(\CCC)C(=O)O

Procedure:
1425 g of glycerol are placed in a four liter flask. 470 g of KOH are added and the mixture is slowly heated, the potassium hydroxide dissolving at approximately 100° C. After reaching a temperature of 140° C., over a period of 11/2 hours 264.4 g of 2-propyl-2-pentene nitrile are added dropwise, the temperature being kept at 140° to 145° C. Slight foaming initially occurs. The reaction mixture is refluxed for 8 hours, accompanied by the escape of ammonia and followed by mixing with 1700 ml of water. After cooling a roughly 2 cm thick, flaky foam layer has deposited on the clear yellow solution. The reaction mixture is acidified to pH 1 with 620 ml of concentrated hydrochloric acid. The separated oil is then taken up with 100 ml of n-hexane and the aqueous phase is again extracted twice with in each case 400 ml of n-hexane. After washing the organic phase with water and drying, a residue of 260 g is obtained by evaporating at 80 mbar and 40° C. Through precision distillation on an active column, 145.4 g of E-2-propyl-2-pentenoic acid is obtained therefrom corresponding to 50.4% of theory. The b.p.15 is 135° to 136° C. The distillate solidifies to a crystalline mass with a melting point of 38° C.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[F:11][C:12]([F:35])([F:34])[C:13]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:14]=1[CH2:15][N:16]1[CH2:22][CH2:21][CH:20]([CH2:23][OH:24])[CH2:19][CH2:18][C:17]1=[O:25].[Cl-].[NH4+]>ClCCl.C(N(CC)CC)C>[F:35][C:12]([F:11])([F:34])[C:13]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:14]=1[CH2:15][N:16]1[C:17](=[O:25])[CH2:18][CH2:19][CH:20]([CH:23]=[O:24])[CH2:21][CH2:22]1
Reactant: O=C1CCC(CO)CCN1Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=CC1CCC(=O)N(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46.3 %

Procedure:
To a solution of DMSO (1.40 g) in dichloromethane (100 mL) was slowly added a solution of oxalyl chloride (2.48 g) in dichloromethane (200 mL) at −78° C. The reaction mixture was stirred for 5 min, a solution of 1-[2,4-bis(trifluoromethyl)benzyl]-5-(hydroxymethyl)azepan-2-one (6.0 g) in dichloromethane (100 mL) was added dropwise, and the mixture was stirred for 15 min. Triethylamine (8.2 g) was added and the mixture was allowed to warm to room temperature. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (2.76 g).
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[NH:6][N:5]=[C:4]2[CH2:9][O:10][C:11]3[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[C:14]([CH:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[CH:13][C:12]=3[N:3]12>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][CH:2]1[C:7](=[O:8])[NH:6][N:5]=[C:4]2[CH2:9][O:10][C:11]3[CH:16]=[C:15]([C:17]([F:18])([F:20])[F:19])[C:14]([CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[CH:13][C:12]=3[N:3]12
Reactant: CC1C(=O)NN=C2COc3cc(C(F)(F)F)c(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1C(=O)NN=C2COc3cc(C(F)(F)F)c(C4CCNCC4)cc3N21

Procedure:
A solution of tert-butyl 4-(1-methyl-2-oxo-8-(trifluoromethyl)-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)piperidine-1-carboxylate (0.01 g, 0.021 mmol) in DCM (5 mL) and TFA (1 mL) was stirred for 1 h at ambient temperature. The solvent was removed in vacuo to give 1-methyl-9-(piperidin-4-yl)-8-(trifluoromethyl)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one trifluoacetic acid salt as a pale yellow solid (0.01 g, 97%). LC/MS (Table 1, Method 5) Rt=3.057 min.; MS m/z: 369 [M+H]+.
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:11][CH:12]([C:17]1[C:18]([CH:36]([CH3:38])[CH3:37])=[N:19][C:20]2[C:21]([CH3:35])([CH3:34])[CH2:22][NH:23][CH2:24][C:25]=2[C:26]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:13]([O:15][CH3:16])=[O:14])([CH3:10])([CH3:9])[CH3:8].[C:39]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[C:39]1([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:44]=[CH:43][C:42]([N:23]2[CH2:22][C:21]([CH3:35])([CH3:34])[C:20]3[N:19]=[C:18]([CH:36]([CH3:38])[CH3:37])[C:17]([CH:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])[C:13]([O:15][CH3:16])=[O:14])=[C:26]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C:25]=3[CH2:24]2)=[CH:41][CH:40]=1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CNCC2(C)C
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(OC(C)(C)C)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CN(c1ccc(-c3ccccc3)cc1)CC2(C)C
Reaction time: 0.08 h
Yield: 84.8 %

Procedure:
A mixture of Cu(OAc)2 (16.42 mg, 0.090 mmol) and pyridine (7 μl, 0.09 mmol) in CH2Cl2 (1 mL) was stirred for 5 min. Added to this were methyl 2-(tert-butoxy)-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetate (intermediate 5) (20 mg, 0.045 mmol), 4-biphenylboronic acid (17.90 mg, 0.09 mmol) and 34 mg molecular sieves. After stirring uncovered for 18 h, the mixture was adsorbed directly onto silica gel and was purified by flash column chromatography (Biotage; 0%-50% EtOAc/hexane) to give methyl 2-(6-([1,1′-biphenyl]-4-yl)-4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-(tert-butoxy)acetate (22.7 mg, 84% yield) as a colorless oil. LCMS (M+H) calcd for C38H44FN2O3: 595.33. found: 595.4. 19F NMR (500 MHz, Methanol d4) δ ppm: −113.055.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.[C:21]1(=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:30])[NH:22]1>>[O:31]=[C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:30])[N:22]1[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CN(C(=O)Oc1ccc(CCO)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(CCN2C(=O)c3ccccc3C2=O)cc1)c1ccccc1
Yield: 39 %

Procedure:
The title compound was prepared in 39% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and isoindole-1,3-dione. NMR (400 MHz; CDCl3): δ 2.98 (t, 2H), 3.41 (br s, 2H), 3.89 (t, 3H), 7.04 (br d, 2H), 7.20-7.40 (m, 7H), 7.68-7.71 (m, 2H), 7.80-7.83 (m, 2H); HPLC-MS: m/z=401.1 (M+1); Rt=4.41 min.
Reaction SMILES: [C:1]1([CH:7]([CH3:12])[CH2:8][C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](Cl)(=[O:17])[CH:14]([CH3:16])[CH3:15]>>[C:13]([C:4]1[CH:5]=[CH:6][C:1]([CH:7]([CH3:12])[CH2:8][C:9](=[O:11])[CH3:10])=[CH:2][CH:3]=1)(=[O:17])[CH:14]([CH3:16])[CH3:15]
Reactant: CC(=O)CC(C)c1ccccc1
Reactant: CC(C)C(=O)Cl
Product: CC(=O)CC(C)c1ccc(C(=O)C(C)C)cc1

Procedure:
As in Example 1 except using 4-phenyl-2-pentanone instead of benzyl acetone, and iso butyryl chloride instead of benzoyl chloride b.p. 130-134 (0.4 mm).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:13]2[N:9]([CH2:10][CH2:11][CH2:12]2)[CH2:8][CH2:7]1)=O)C>C1COCC1.C(OCC)C.O>[CH:6]1([CH2:4][OH:3])[CH:13]2[N:9]([CH2:10][CH2:11][CH2:12]2)[CH2:8][CH2:7]1
Reactant: CCOC(=O)C1CCN2CCCC12
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: OCC1CCN2CCCC12
Reaction time: 12 h

Procedure:
Lithiumaluminumhydride (0.3 g) was added to a solution of hexahydropyrrolizine-1-carboxylic acid ethyl ester (0.97 g) in THF (3 ml). After 12 hours, the reaction mixture was diluted with diethyl ether and hydrolyzed by cautious addition of water (0.7 ml). The resulting precipitate was filtered off and the filtrate was concentrated. The product with the molecular weight of 141.21 (C8H15NO); MS (ESI): 142 (M+H+) was obtained in this way.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C:14]2[NH:15][CH:16]=[CH:17][N:18]=2)[CH:8]=1)C.[ClH:20]>C(#N)C>[ClH:20].[NH:15]1[CH:16]=[CH:17][N:18]=[C:14]1[CH2:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[O:6][CH2:5][C:4]([OH:19])=[O:3]
Reactant: CCOC(=O)COc1cccc(Cc2ncc[nH]2)c1
Agent: Cl
Solvent: CC#N
Product: O=C(O)COc1cccc(Cc2ncc[nH]2)c1

Procedure:
Hydrolysis of 3-(1-imidazolylmethyl)phenoxyacetic acid ethyl ester free base with concentrated hydrochloric acid according to the method of Example 7 gave 3-(1-imidazolylmethyl)phenoxyacetic acid hydrochloride, m.p. 179°-181° C. (from aqueous acetonitrile). Found: C, 52.23, H, 4.84, N, 10.65. C12H12N2O3.HCl requires: C, 53.64, H, 4.88, N, 10.43%.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[S:2].[O:13]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CN=C1.[NH2:32][C:33]1[NH:37][N:36]=[C:35]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([S:45]([NH2:48])(=[O:47])=[O:46])=[CH:41][CH:40]=2)[N:34]=1>C(#N)C.CN(C=O)C>[O:13]([C:20]1[CH:21]=[CH:22][C:23]([NH:24][C:1]([N:37]2[C:33]([NH2:32])=[N:34][C:35]([NH:38][C:39]3[CH:40]=[CH:41][C:42]([S:45](=[O:46])(=[O:47])[NH2:48])=[CH:43][CH:44]=3)=[N:36]2)=[S:2])=[CH:25][CH:26]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1nc(Nc2ccc(S(N)(=O)=O)cc2)n[nH]1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CC#N
Product: Nc1nc(Nc2ccc(S(N)(=O)=O)cc2)nn1C(=S)Nc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
Thiocarbonyldiimidazole (0.56 mmol, 1.5 equivalent) was added to a solution of 4-phenoxy aniline (0.6 mmol, 1.6 equivalents) and imidazole (0.07 mmol, 0.2 equivalent) in acetonitrile (5 ml). The reaction mixture was stirred at room temperature for three hours. 4-(5-Amino-1H-[1,2,4]triazol-3-ylamino)-benzenesulfonamide (0.37 mM, 1 equivalent) was added in one portion. The reaction mixture was stirred at 50° C. for 16 hours. After addition of DMF (1 ml), the reaction mixture was stirred at 80° C. for one hour. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with EtOAc:pentane (30:70 to 0:100) to afford the title compound (40 mg; 40% yield). 1H NMR (400 MHz, DMSO-d6) 7.05-7.18 (6H, m), 7.20-7.23 (1H, t), 7.40-7.50 (4H, m), 7.70-7.75 (2H, d), 7.80-7.85 (2H, d), 8.45-8.50 (2H, s), 9.80-9.85 (1H, s), 10.90 (1H, s); MS (ES+) m/e=482
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[CH3:8][O:9][CH2:10][CH2:11]O.N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:2](=[O:3])([OH:9])[OH:4].[Cl:7][CH:5]([CH2:11][CH2:10][O:9][CH3:8])[CH3:6]
Reactant: CC(Cl)OC(=O)Cl
Reactant: COCCO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COCCC(C)Cl
Product: O=C(O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
1-Chloroethyl chloroformate (28.6 g, 0.2 mol) and 2-methoxyethanol (13.7 g, 0.18 mol) were dissolved in chloroform (220 ml) at 0° C. Pyridine (15.8 g, 0.2 mol) was added dropwise during 45 minutes maintaining the temperature below 12° C. After stirring at room temperature for 2 hours the mixture was washed three times with 1 normal hydrochloric acid, once with a saturated sodium hydrogen carbonate solution and finally twice with water. The organic phase was dried with magnesium sulfate and the solvent was removed at reduced pressure. The residue was distilled in vacuo. Yield: 75%. 1H-NMR: delta=1.76 (CHCH3); 3.27 (OCH3); 3.55 (CH2OCH3); 4.27 (COOCH2); 6.51 (CH).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:19]2[NH:20][CH2:21][C:22]([OH:30])=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=2)[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO>[CH2:1]([O:8][C:9]([NH:11][C:12]1([C:19]2[NH:20][CH2:21][C:22]([O:30][S:32]([CH3:31])(=[O:34])=[O:33])=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=2)[CH2:17][CH2:16][CH:15]([O:18][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=C(O)CNC(C2(NC(=O)OCc3ccccc3)CCC(O)CC2)=N1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(OS(C)(=O)=O)CNC(C2(NC(=O)OCc3ccccc3)CCC(OS(C)(=O)=O)CC2)=N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 853.1 %

Procedure:
To a stirred solution of ethyl 2-(1-(benzyloxycarbonylamino)-4-hydroxycyclohexyl)-5-hydroxy-1,6-dihydropyrimidine-4-carboxylate (1.75 g, 4.05 mmol) in THF (25 mL) was added methanesulfonyl chloride (0.94 mmol, 12.17 mmol) and triethylamine (1.7 mL, 12.75 mmol) at 5° C. and the mixture stirred at room temperature for 18 h. The resulting white precipitate was filtered off and washed with THF. The filtrate and washings were concentrated to afford an amber oil. A solution of this oil in methanol (20 mL) was treated with K2CO3 (560 mg, 4.05 mmol) at room temperature for 3 h. The mixture was then concentrated and the residue dissolved in ethyl acetate (200 mL), washed with 1N HCl (100 mL) followed by brine (100 mL) and then dried (Na2SO4), filtered and concentrated to give 2.3 g of the title compound as an amber oil, which was used in the next step without further purification. LCMS (M+H)=588.41.
Reaction SMILES: [NH2:1][C:2]1[CH:42]=[CH:41][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:40]=[CH:39][C:19]([CH2:20][N:21]([CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:43])[CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:54](Cl)([O:56]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:65][C:66]1[CH:70]=[C:69]([CH3:71])[O:68][N:67]=1>O1CCCC1>[F:43][C:4]1[CH:3]=[C:2]([NH:1][C:54]([NH:65][C:66]2[CH:70]=[C:69]([CH3:71])[O:68][N:67]=2)=[O:56])[CH:42]=[CH:41][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[CH:40]=[CH:39][C:19]([CH2:20][N:21]([CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[CH:18][CH:17]=3)[S:15][C:8]=12
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COCCOCCOCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cc1)C(=O)OC(C)(C)C
Reactant: Cc1cc(N)no1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCCOCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)Nc5cc(C)on5)cc4F)c3s2)cc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 102.6 %

Procedure:
To a solution of 366 (0.15 g, 0.25 mmol) and DIPEA (0.11 mL, 0.080 g, 0.61 mmol) in tetrahydrofuran (50 mL) at 0° C. was added triphosgene (0.029 g, 0.098 mmol) and the resulting solution was stirred for 1 h at 0° C. 3-Amino-5-methylisoxazole (0.025 g, 0.25 mmol) was added and the mixture was warmed to room temperature and stirred for 3 h, then quenched with 1 mL of water and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water; the organic phase was collected, washed with brine, dried over MgSO4, filtered and concentrated. The product was purified by silica gel chromatography (eluent 2% MeOH in EtOAc) to give 367 (0.074 g, 4% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1([CH2:21][CH3:22])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8](=O)[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19].CO.Cl.[CH3:27][S:28]([NH:31][NH2:32])(=[O:30])=[O:29]>O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1([CH2:21][CH3:22])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8](=[N:32][NH:31][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19]
Reactant: CS(=O)(=O)NN
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3=O
Agent: Cl
Solvent: CO
Solvent: O
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3=NNS(C)(=O)=O
Reaction time: 0.02 h

Procedure:
To the ester of Example 4, Step B (0.5 g, 1.6 mmol) was added 10 ml MeOH, 0.4 ml 1N HCl and 0.37 ml H2O. The mixture was stirred one minute followed by addition of CH3SO2NHNH2 all at once. After overnight stirring, the MeOH was evaporated and additional water was added. This aqueous phase was twice extracted with CH2Cl2. The organic phase was concentrated to a crude solid and purified by flash chromatography using CH2Cl2 --EtOAc 95-5 as eluent. The product 0.33 g, was obtained as a solid m.p. 80°-82° C.